Chronic stress contributes to inflammation, which predisposes to the development of persistent mood disorders and behavioral and cognitive impairment. Immune cells use cytokine proteins to transmit inflammatory signals from the periphery to the brain. Cytokines play a critical role in mood and behavior changes caused by neuroinflammation.
Research confirms that immune activation is associated with behavioral disorders:
- In humans, endotoxin administration causes changes in behavior and cognitive abilities.
- In rodents, cytokines or exposure to chronic stress lead to increased neuroinflammation and behavioral changes.
- Chronic stress and repetitive social abuse contribute to neuroinflammation, cognitive impairment, and mood and behavioral disturbances such as despair, anhedonia, anxiety, and reduced social activity.
- Suppression of neuroimmune activation prevents stress-induced behavioral disturbances.
Interferons in The CNS: Protective and Pathogenic Role
Type I interferons (IFN-I) play an important role in activating innate and adaptive immunity. The most studied members of the IFN-I family are IFN-alpha and IFN-beta. They both regulate the peripheral inflammatory response and promote the recruitment of immune cells to the foci of infection and stimulate their effector functions.
IFN-I plays a pathogenic or protective role in the central nervous system, depending on the concentration. IFN-I has antiviral and immunomodulatory effects. In addition, IFN-beta is critical for neuronal homeostasis. IFN-beta is a growth factor for neural progenitor stem cells and enhances their differentiation into oligodendroglia. In patients with multiple sclerosis, IFN-beta therapy prevents and reduces relapses and reduces cognitive loss. However, treatment with IFN-beta exacerbates depression in patients with multiple sclerosis and a history of depression.
Type I interferons play an important role in maintaining homeostasis of the central nervous system and regulating emotions:
- Treatment with IFN-alpha is often associated with developing symptoms of depression, fatigue, anxiety, and cognitive impairment in patients with multiple sclerosis and hepatitis C.
- Treatment with IFN-beta causes behavioral disturbances and depressive symptoms in patients with multiple sclerosis.
- Administration of IFN-beta to healthy volunteers resulted in decreased motivation.
- An increase in IFN-I signaling has been observed in the blood of depressed patients.
- In rodents, peripheral administration of IFN-I induced depression-like behavior and suppressed neurogenesis but increased the expression of IFN-I-stimulated genes (ISG) in the hippocampus.
Chronic stress and increased IFN-I activity enhance microglial activation. Microglia are immune cells in the brain. Chronic stress activates microglia in the hippocampus and prefrontal cortex. These areas of the brain regulate mood and social and cognitive functions. In addition, microglia are activated in response to an increase in IFN-I activity, leading to a deterioration in the transmission of nerve impulses.
Chronic stress increases levels of complement protein C3. The complement system is part of the innate immune system, which comprises protective blood proteins. The complement system plays a key role in nerve impulse transmission and inflammation. In mice, chronic stress increased C3 levels and impaired neural transmission in the prefrontal cortex.
Type I Interferon Controls Neuroinflammation and Behavioral Disturbances in Chronic Stress Through The C3 Protein Signaling Pathway
American scientists conducted a study on mice. To simulate chronic stress, mice were kept immobile for 2 hours a day for 21 days.
The scientists found that stress significantly increased serum levels of IFN-beta in mice, and systemic blockade of IFN-I signaling attenuated stress-induced macrophage infiltration into the prefrontal cortex and behavioral abnormalities. Complement protein C3 is also responsible for IFN-beta-induced neuroinflammation and behavioral changes.
In addition to mice, the scientists examined the brains of suicidal subjects. The scientists found a significant increase in ISG expression in the prefrontal cortex. ISG levels correlated with C3 and inflammatory markers.
Research Output
- Suppression of IFN-I signals attenuates chronic stress-induced impairments in social behavior and spatial memory.
Chronic stress increased IFN-beta levels in mice but did not alter IFN-alpha levels.
Mice with chronic stress were less likely to socialize than mice in the control group.
Chronically stressed mice were injected with an antibody against type I interferon receptor (IFNAR). This blocking of IFN-I signaling improved social interaction in chronically stressed mice.
The spatial memory of mice was tested using a Y-shaped maze. Normally, mice visit a new arm of the maze instead of going to the previously visited arm. Spontaneous alternation of labyrinth arms is considered an indicator of spatial memory.
Chronic stress did not change physical activity. However, mice with chronic stress alternated arms of the maze much less frequently than mice in the control group. Blocking IFN-I signaling caused the percentage of maze arm alternation to equalize between chronically stressed and control mice.
- Blocking IFN-I signaling attenuates chronic stress-induced macrophage infiltration and increases ISG levels in the prefrontal cortex.
- Blocking IFN-I signaling attenuates chronic stress-induced changes in serum inflammatory markers and pro-inflammatory and anti-inflammatory macrophage markers in the prefrontal cortex and hippocampus.
Elevated serum levels of pro-inflammatory cytokines, especially TNF-α and IL-1-β, increase susceptibility to neuropsychiatric disorders such as depression. Moreover, chronic stress conditions increase serum levels of pro-inflammatory markers.
Chronic stress significantly increased the serum levels of TNF-α and IL-1-β in mice. Blocking IFN-I signaling attenuated the increase in TNF-α and IL-1-β levels.
As a result of disruption of tissue homeostasis, macrophages switch between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Under chronic stress, M1 markers significantly increased in mice’s prefrontal cortex and hippocampus, but M2 markers did not change. Blocking the transmission of IFN-I signals weakened the magnification of M1 markers and increased M2 markers.
- Complement protein C3 is involved in IFN-beta-dependent neuroinflammation and impaired social behavior.
Chronic stress significantly increased C3 levels in mice’s prefrontal cortex and hippocampus.
C3-deficient and wild-type mice were injected with IFN-beta to study social behavior and spatial memory. Mice with C3 deficiency socialized better, but C3 deficiency did not affect spatial memory.
Also, C3 deficiency attenuated IFN-beta-associated macrophage infiltration into the prefrontal cortex and hippocampus.
- Depression increases the expression of genes stimulated by IFN-I in the prefrontal cortex.
Conclusions
Chronic stress increases serum levels of IFN-beta and causes impairments in social behavior and spatial memory.
IFN-beta-induced behavioral disturbances and neuroinflammation are dependent on complement protein C3. Depressed suicidal subjects have elevated levels of IFN-I-stimulated genes in the prefrontal cortex, which correlates with C3 and inflammatory markers.
IFN-I signaling supposes chronic stress-induced infiltration of macrophages into the brain and behavioral disturbances. Influencing the IFN-I signaling pathway may help patients with elevated immune status, often observed in depression.
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